Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

Inclusion Criteria:

• Subjects must be able to understand the nature of this trial and provide writteninformed consent, prior to any study specific procedures; patients with ImpairedDecision Making Capacity (IDMC) who have a close caregiver or legally authorizedrepresentative (LAR) may be considered eligible for this study at the treatingphysician's discretion, provided that the physician is reasonably sure that thepossible risks and benefits of the study are clear and that the patient will takethe drug as prescribed

• Subjects must be diagnosed with a glioma, cholangiocarcinoma or other solidmalignant tumor that has progressed despite standard therapy, or for which noeffective standard therapy exists, with biopsy-confirmed evidence of an IDH1 or IDH2mutation associated with neomorphic activity of the encoded proteins; patients musthave IDH1 or IDH2 mutation which must be detected in a clinical accreditedlaboratory using a Food and Drug Administration (FDA)-approved molecular test or avalidated deoxyribonucleic acid (DNA)-based assay conducted in a Clinical LaboratoryImprovement Amendments (CLIA)-certified laboratory; only specific mutations thatlead to a neomorphic phenotype will be eligible for enrollment, and include IDH1:R132V, R132G, R132S, R132L, R132C and R132H; IDH2: R140W, R140L, R140Q, R172W,R172G, R172S, R172M, R172K

• Patients must have tumors determined to be easily accessible for biopsy and must bewilling to have serial biopsies (with a third biopsy upon evidence of diseaseprogression); in case of multiple lesions, tumor biopsies will be performed on themost accessible site of disease; all possible precautions to avoid complicationswill be taken, including discussions in multidisciplinary meetings, if needed;patients affected by glioma will not be considered for study biopsies

• Patients must be willing to undergo extra blood sampling for correlative studies

• Subjects with extracranial disease must have evaluable disease by ResponseEvaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); subjects affected byglioma must have evaluable disease by Response Assessment in Neuro-Oncology Criteria (RANO) criteria

• For subjects with glioma, specific inclusion criteria are as follows:

• The disease should be recurrent or transformed glioma; subjects must not havehad prior surgery (biopsy allowed) or radiation therapy within 3 weeks ofenrollment

• There must be an enhancing component of disease, as evaluated on pre-treatmentmagnetic resonance imaging (MRI)

• For patients with World Health Organization (WHO) grade III or IV glioma andprogressive disease < 12 weeks after completion of chemoradiotherapy,progression can be defined by the following set of criteria:

• New enhancement outside of the radiation field (beyond the high-doseregion or 80% isodose line)

• If there is unequivocal evidence of viable tumor on histopathologicsampling (e.g., solid tumor areas. i.e., > 70% tumor cell nuclei inareas), high or progressive increase in MIB-1 proliferation index comparedwith prior biopsy, or evidence for histologic progression or increasedanaplasia in tumor);

• Note: Given the difficulty of differentiating true progression frompseudoprogression, clinical decline alone, in the absence of radiographicor histologic confirmation of progression, will not be sufficient fordefinition of progressive disease in the first 12 weeks after completionof concurrent chemoradiotherapy

• For patients with WHO grade III or IV glioma and progressive disease >= 12weeks after completion of chemoradiotherapy, progression can be defined by thefollowing set of criteria:

• New contrast-enhancing lesion outside of radiation field on decreasing,stable, or increasing doses of corticosteroids

• Increase by >= 25% in the sum of the products of perpendicular diametersbetween the first post-radiotherapy scan, or a subsequent scan withsmaller tumor size, and the scan at 12 weeks or later on stable orincreasing doses of corticosteroids

• For patients receiving antiangiogenic therapy, significant increase inT2/fluid attenuated inversion recovery (FLAIR) non-enhancing lesion mayalso be considered progressive disease; the increased T2/FLAIR must haveoccurred with the patient on stable or increasing doses of corticosteroidscompared with baseline scan or best response after initiation of therapyand not be a result of comorbid events (e.g., effects of radiationtherapy, demyelination, ischemic injury, infection, seizures,postoperative changes, or other treatment effects)

• Note: Clinical deterioration alone is not attributable to concurrentmedication or comorbid conditions is sufficient to declare progression oncurrent treatment but not for entry onto a clinical trial for recurrence

• For patients with WHO grade II glioma progression is defined by any one of thefollowing:

• Development of new lesions or increase of enhancement (radiologicalevidence of malignant transformation)

• A 25% increase of the T2 or FLAIR non-enhancing lesion on stable orincreasing doses of corticosteroids compared with baseline scan or bestresponse after initiation of therapy, not attributable to radiation effector to comorbid events

• For subject with extracranial disease, they must have at least one lesion, notpreviously irradiated, that can be accurately measured at baseline as >= 10 mm inthe longest diameter (except lymph nodes which must have short axis >= 15 mm) withcomputed tomography (CT) or magnetic resonance imaging (MRI) or >= 10 mm withcalipers by clinical exam OR at least one lesion (measurable and/or non-measurable)that can be accurately assessed by CT/MRI/clinical exam at baseline and follow upvisits

• Subjects must have progressive cancer at the time of study entry; prior experimental (non-FDA approved) therapies (other than drugs that share the same target) andimmunotherapies are allowed; patients must not have received these therapies for 30days or five half-lives of the drug (whichever is less) prior to the initiation ofstudy treatment; toxicities from these therapies should have recovered to =< grade 1, with the exception of stable chronic grade 2 that is not overlapping withpresumed toxicities of olaparib

• Female/male of age >= 18 years. This is because no dosing or adverse event data arecurrently available on the use of olaparib in patients < 18 years of age, childrenare excluded from this study, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG) 0-2 (Karnofsky >= 50%)

• Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28days prior to administration of study treatment)

• Leukocytes >= 3,000/mcL (within 28 days prior to administration of study treatment)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior toadministration of study treatment)

• Platelet count >= 100 x 10^9/L (within 28 days prior to administration of studytreatment)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 daysprior to administration of study treatment)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present inwhich case they must be =< 5 x ULN (within 28 days prior to administration of studytreatment)

• Creatinine clearance estimated using the actual body weight and Cockcroft-Gaultequation of >= 51 mL/min (within 28 days prior to administration of study treatment)

• Patients must have a life expectancy >= 16 weeks

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up

• No previous treatment with the specific assigned study drug or any other PARPinhibitor

• Prior radiation therapy is allowed; patients must not have received radiationtherapy within 3 weeks prior to the initiation of study treatment

• Women of child-bearing potential are expected to use highly effective contraceptionduring the study and for 1 month after the last dose of study drug; postmenopausalor evidence of non-childbearing status for women of childbearing potential: negativeurine or serum pregnancy test within 28 days of study treatment and confirmed priorto treatment on day 1; postmenopausal is defined as one or more of the following:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in thepost-menopausal range for women under 50

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with > 1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• Male patients and their partners, who are sexually active and of childbearingpotential, must agree to the use of two highly effective forms of contraception incombination, throughout the period of taking study treatment and for 3 months afterlast dose of study drug(s) to prevent pregnancy in a partner

Exclusion Criteria:

• Patients should not enter the study if any of the following exclusion criteria arefulfilled

• Involvement in the planning and/or conduct of the study

• Previous enrollment in the present study

• Participation in another clinical study with an investigational product during thelast 30 days or five half-lives of the drug (whichever is less) prior to theinitiation of study treatment (6 weeks for nitrosoureas or mitomycin C)

• Any previous treatment with PARP inhibitor, including olaparib

• Patients receiving any systemic chemotherapy or radiotherapy (except for palliativereasons) within 3 weeks prior to study treatment

• Other malignancy within the last 5 years except: adequately treated non-melanomaskin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma insitu (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors includinglymphomas (without bone marrow involvement) curatively treated with no evidence ofdisease for >= 5 years; patients with a history of localized triple negative breastcancer may be eligible, provided they completed their adjuvant chemotherapy morethan three years prior to registration, and that the patient remains free ofrecurrent or metastatic disease

• Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec orfamily history of long QT syndrome

• Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the requiredwashout period prior to starting olaparib is 2 weeks; because the lists of theseagents are constantly changing, it is important to regularly consult a frequentlyupdated drug information reference; medical reference texts such as the Physicians'Desk Reference may also provide this information; as part of the enrollment/informedconsent procedures, the patient will be counseled on the risk of interactions withother agents, and what to do if new medications need to be prescribed or if thepatient is considering a new over-the-counter medicine or herbal product

• Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) ormoderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents; because the lists of these agents are constantly changing,it is important to regularly consult a frequently updated drug informationreference; medical reference texts such as the Physicians' Desk Reference may alsoprovide this information; as part of the enrollment/informed consent procedures, thepatient will be counseled on the risk of interactions with other agents, and what todo if new medications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Persistent toxicities caused by previous cancer therapy; toxicities should haverecovered to =< grade 1, excluding alopecia and stable chronic grade 2 toxicity thatis not overlapping with presumed toxicities of olaparib

• Patients with myelodysplastic syndrome/acute myeloid leukemia or with featuressuggestive of MDS/AML

• Patients with symptomatic uncontrolled brain metastases; a scan to confirm theabsence of brain metastases is not required; the patient can receive a stable doseof corticosteroids before and during the study if these were started at least 4weeks prior to treatment; patients with spinal cord compression unless considered tohave received definitive treatment for this and evidence of clinically stabledisease for 28 days; patients with known uncontrolled brain metastases should beexcluded from this clinical trial because of their poor prognosis and because theyoften develop progressive neurologic dysfunction that would confound the evaluationof neurologic and other adverse events

• Major surgery within 2 weeks of starting study treatment; effects from surgeriesshould have recovered to =< grade 1, with the exception of stable chronic grade 2that is not overlapping with presumed toxicities of olaparib

• Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection; examplesinclude, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstablespinal cord compression, superior vena cava syndrome, extensive interstitialbilateral lung disease on high resolution computed tomography (HRCT) scan or anypsychiatric disorder that prohibits obtaining informed consent and would limitcompliance with study requirements

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication

• Women who are actively breast feeding

• Immunocompromised patients, e.g., patients who are known to be serologicallypositive for human immunodeficiency virus (HIV); HIV-positive patients oncombination antiretroviral therapy are ineligible because of the potential forpharmacokinetic interactions with Olaparib; in addition, these patients are atincreased risk of lethal infections when treated with marrow-suppressive therapy;appropriate studies will be undertaken in patients receiving combinationantiretroviral therapy when indicated

• Patients with a known hypersensitivity to olaparib or any of the excipients of theproduct; history of allergic reactions attributed to compounds of similar chemicalor biologic composition to olaparib

• Patients with known active hepatitis (i.e. hepatitis B or C) due to risk oftransmitting the infection through blood or other body fluids

• Previous allogeneic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)

• Whole blood transfusions in the last 120 days prior to entry to the study (packedred blood cells and platelet transfusions are acceptable)

• Patients who are receiving any other investigational agents

• Pregnant women are excluded from this study because olaparib is an agent with thepotential for teratogenic or abortifacient effects; because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with olaparib, breastfeeding should be discontinued if the mother is treatedwith olaparib

• Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), orfeatures suggestive of MDS/AML